| Autor: |
Richard L. Mackman, Rao Kalla, Darius Babusis, Jared Pitts, Kimberly T. Barrett, Kwon Chun, Venice Du Pont, Lauren Rodriguez, Jasmine Moshiri, Yili Xu, Michael Lee, Gary Lee, Blake Bleier, Anh-Quan Nguyen, B. Michael O’Keefe, Andrea Ambrosi, Meredith Cook, Joy Yu, Elodie Dempah, Elaine Bunyan, Nicholas C. Riola, Xianghan Lu, Renmeng Liu, Ashley Davie, Tien-Ying Hsiang, Michael Gale, Anita Niedziela-Majka, Joy Y. Feng, Charlotte Hedskog, John P. Bilello, Raju Subramanian, Tomas Cihlar |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.04.28.538473 |
| Popis: |
Remdesivir1is an amidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells thereby forming the bioactive triphosphate2-NTP.2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for1have prompted interest in oral approaches to generate2-NTP. Here we describe the discovery of a 5’-isobutyryl ester prodrug of2 (GS-5245, Obeldesivir,3) that has low cellular cytotoxicity and three to seven-fold improved oral delivery of2in monkeys. Prodrug3is cleaved pre-systemically to provide high systemic exposures of2that overcome its less efficient metabolism to2-NTPleading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350-400 mg twice-daily. Importantly, all SARS-CoV-2 variants remain susceptible to2which supports development of3as a promising COVID-19 treatment. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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